NYUThe Magazine of New York UniversitPhy School of Medicineysiciawinter 2012–2013n volume 64 • No.

Missing 2 a crucial Target Biopsies for prostate cancer often overlook dangerous lesions

PLUS

The Truth About Low Testosterone The Male Biological Clock Neuroscience and the Love Song of Finches Help Us Make Dreams Come True

EVERY ASPIRING PHYSICIAN DREAMS OF THE DAY SOMEONE WILL MAKE A GIFT ONLINE CALL HIM OR HER “DOCTOR” FOR THE FIRST TIME. But getting there Please visit www.nyu.edu/alumni. takes a lot more than hard work and dedication—it takes resources. By contributing to the NYU School of Medicine Alumni Campaign, you help To discuss special ensure that our next generation of physicians will have access to the best giving opportunities, teaching and research, along with a competitive fi nancial assistance package. call Anthony J. Grieco, MD, Associate Dean for Alumni Relations, When you make a gift, you help us guarantee that all of our students will at 212.263.5390. have the means to complete our rigorous education. One day, you may even have the privilege of addressing them yourself as “Doctor.”

Thank you for your generosity. The Magazine of New York University School of Medicine WINTER 2012–2013 volume 64 no. NYUPhysician 2

New York University Martin Lipton, Esq. Chairman, “We’ve made progress. But Board of Trustees if anyone thinks that we’ve John Sexton President optimized screening by using a nonspecific marker and Robert Berne Executive Vice President randomly placing 12 needles for Health • and taking 12 specimens, NYU Langone Medical Center then he's naive.” Kenneth G. Langone Chairman, Board of Trustees

Robert I. Grossman, MD Dean and Chief Executive Officer Cover Stories • NYU Physician Hitting the Bull’s-Eye in Prostate Cancer Steven B. Abramson, MD 10 New imaging techniques Anthony J. Grieco, MD Editors, Science pioneered at NYU Langone and Medicine departments distinguish deadly lesions.  Marjorie Shaffer 02 From the Dean The Truth About Low T Editor Men’s Health As testosterone replacement 14 therapy grows more popular, Nicole Dyer Contributing Editor 03 The Balm After the Storm debate rages over its safety and Hurricane Sandy inflicts unprecedented efficacy. How can patients and Sherry Zucker damage on the Medical Center. physicians sort out the science Print Production from the hype? Coordinator 06 News From Medicine Segal Savad Design • Regional Differences Found in Imaging The Risks of Fathering Art Direction • Paying the Toll in Pancreatic Cancer a Child Later in Life • New Hope for Diagnosing Mesothelioma 20 A growing body of research Nancy E. Sherman • The Synapse You Can’t Live Without indicates that certain brain Copy Editor disorders in children are related • 28 Faculty Conversation to their father’s age. On the Cover: Q&A with Richard Novick, MD illustration by The Melody of Finches STUART BRIers 30 Faculty News A neuroscientist learns how • Dean’s Honors Day 24 zebra finches perfect their love Master Clinician Philip K. Moskowitz, MD song and, in the process, makes Master Scientist Danny Reinberg, PhD some surprising discoveries Master Educator and Mentor about how neurons hook up. Linda R. Tewksbury, MD Valentine Mott Founders Awardee Larry A. Silverstein • Dr. Llinás Honored • Dr. Tsien Receives Neuroscience Award • Dr. Littman Elected to Institute of Medicine

32 Obituary Dr. Robert Porges tuart br i ers i on by S tuart Illustrat

NYU Physician WINTER 2012–2013 1 Message from the Dean Men’s & CEO Health by the Numbers Men’s Health 241,740 Although men are living longer and enjoying Estimated number of prostate cancer healthier lives, there is much room for cases diagnosed among U.S. men in improvement. This issue of NYU Physician 2012, second only to skin cancer* highlights some of the health challenges men encounter as they age. Prostate cancer is the second leading cause of cancer death, 2.5 million but today in the United States doctors are Estimated number of U.S. men diagnosed with prostate cancer still unable to distinguish reliably between who are still alive** aggressive and nonaggressive tumors. You will read about how our urologists and radiologists are working to solve this 1 in13 urgent problem, proving once again that Lifetime odds of a man's collaborative teamwork can yield meaningful developing lung cancer* results in the clinic. Our story on hypogonadism, or low testosterone, explores whether testosterone replacement therapy works and who should receive it, an important and relatively recent issue in men’s health. 79% Another story describes the emerging evidence for a male biological Percent of all fatal suicides clock, a phrase almost unheard of a mere decade ago. committed by males** You will also find a remarkable story about a neuroscientist who is learning about the neuronal basis of behavior through the love song of finches, a thoughtful Q&A with Dr. Richard Novick, one of our 307,225 Number of U.S. men killed by heart pioneering microbiologists, and the latest research from our laboratories. disease in 2009, accounting for I cannot end this letter without mentioning Hurricane Sandy. The roughly 1 in every 4 male deaths*** accompanying story provides many details about the heroism of our healthcare providers during the night the hurricane slammed into our Medical Center. The following weeks brought many losses and many 30 million lessons, but it also highlighted what I will always remain thankful Number of U.S. men with for, the dedication of the entire NYU Langone community and our erectile dysfunction**** determination to prevail. Eugene Braunwald (’52), the Distinguished Hersey Professor of Medicine at Harvard and one of our most illustrious alumni, wrote a 25% Percent of men ages 35 to 44 who letter to the class of 2016 that bears repeating here. “I admire enormously have high blood pressure***** the courage of the entire NYU Medical School family to deal with this extraordinary event. I know from personal experience that from adversity comes strength and that my beloved alma mater will be even better and stronger after the recovery from this devastating event.” I 20 to 30 or more Number of times per hour that men wholeheartedly concur. • can momentarily stop breathing, during a bout of sleep apnea****

*American Cancer Society **Centers for Disease Control and Prevention ***National Vital Statistics Reports ****National Institutes of Health Dean & Ceo robert i. grossman, md *****American Heart Association

NYU Physician photograph by 2 WINTER 2012–2013 JOHN ABBOTT The Balm After the Storm NYU Langone confronts the worst crisis in its history.

On Monday, October 29, 2012—one operations, the year after Hurricane Irene forced NYU Incident Command Langone Medical Center to evacuate its Team (ICT)— patients and close its doors—Hurricane administrators Sandy did one better, plunging the Medical charged with Center into the worst crisis of its history. hospital-wide crisis Extensive damage to the main campus management— forced the closure of Tisch Hospital, the began meeting and Rusk Institute of Rehabilitation Medicine, conferring frequently. and our three research buildings—the The ICT and Skirball Institute of Biomolecular Medicine, executive leadership the Joan and Joel Smilow Research Center, faced an impossibly and the Medical Sciences Building—for complex calculation. more than two months. The storm also Would more than shuttered Bellevue Hospital Center and the 575 inpatients, Manhattan VA Medical Center, both home particularly those to many of NYU Langone’s researchers who were most frail, and clinicians and our primary teaching Ambulances lined up outside be less at risk if they were sheltered in place affiliates. All told, the unprecedented the Medical Center to receive during the storm? “There are significant risks evacuated patients. disaster disrupted operations at the heart to transferring patients,” Dr. Birnbaum of our three core missions: education, notes. “It’s the least desirable option.” research, and patient care. filled its basement. For some researchers, On the previous Friday, NYU Langone On the night of the disaster, 322 patients this represented the loss of years of work. In began to discharge all medically stable were safely transferred to 14 other the aftermath of the hurricane, every effort patients, reducing its census to 325. At hospitals within 13 hours—a physical and was made to salvage as much as possible in the same time, Real Estate Development + logistical challenge of epic proportions. research laboratories. “I have been inspired Facilities also began implementing a wide Some 1,000 medical and professional by the entire NYU Langone community,” range of measures to secure the physical personnel—including nurses, physicians, said Dafna Bar-Sagi, PhD, senior vice plant and mitigate the storm’s impact. fellows, residents, medical students, president and vice dean for science, “not As an additional precaution, the Medical and therapists—along with firefighters the least of which are our postdocs and Center announced on Sunday, October 28, and countless volunteers from our grad students. Armed with positive the cancellation of all scheduled surgeries administrative and support staff rose to the attitudes, determination, and apparently and procedures—with the exception of challenge, evacuating every single patient. quite strong biceps, they carried more than emergent procedures—through Tuesday, Another population was also at risk. 3,500 pounds of dry ice up hundreds of October 30, and the closure of all off- Tens of thousands of genetically altered stairs and then repeated this and many campus ambulatory care centers and mice used to study myriad diseases other tasks. Their efforts saved countless on-campus physician offices. To ensure were housed in the basements of two specimens and samples, bolstering the that the patient census be kept at a of the research facilities. The power future success of our research programs.” minimum throughout the storm, Tisch outage damaged sensitive, sophisticated Days before the storm’s arrival, the Medical Hospital’s Emergency Department was or i Donaghy equipment, compromised ongoing Center began implementing a wide range of also closed. “Based on all the preparations experiments, and destroyed specimens and measures designed to mitigate its impact. we had made, and knowing that we had reagents. Tragically, many of the animals in Led by Bernard Birnbaum, MD, senior vice emergency power in place if needed, we

photograph L photograph the Smilow building were lost when water president, vice dean, and chief of hospital were confident that we could weather the

NYU Physician WINTER 2012–2013 3 storm,” Dr. Birnbaum explains. patients because of their inherently Hurricane Irene, which forced the vulnerable condition. Seven patients were evacuation of NYU Langone in August evacuated from the Laurence D. and Lori 2011, had been dubbed “the storm of the Weider Fink pediatric intensive care unit, century.” But Hurricane Sandy created a six from the congenital cardiovascular storm surge at Battery Park that was 2.68 care unit (CCCU), and 20 from the KiDS feet higher than the record level set in 1821, of NYU Langone Neonatal ICU (NICU). qualifying Sandy—in those terms, at least— The daunting logistics were orchestrated, as the worst storm to hit New York City in in part, by Bret Rudy, MD, associate two centuries. Along Flood Zone A, which professor of pediatrics and vice chair of the includes our campus, the surge rose to Department of Pediatrics. “The evacuation 14½ feet, more than a half foot higher than could not have been so successful without at Battery Park. When the team learned many helping hands,” Dr. Rudy concedes. on Monday night that water had reached “Calling other hospitals to assess buildings on campus, that the entire phone who could take patients, handwriting system was down, and that the emergency summaries of medical charts and histories Sandbags were part of the precautions backup power system was at risk, the by flashlight, notifying and reassuring for the hurricane. writing was on the wall. “The storm surge anxious parents of the situation—none of that crippled the city and overwhelmed our this could have been done in record time defenses occurred over only 30 minutes,” without the superb teamwork of attending Dr Birnbaum notes. “When it became physicians, fellows, residents, medical clear that our emergency power could students, nurses, and so many others.” propose—that the safest way to evacuate be compromised, there was no doubt by Numerous administrative departments the infants would be to carry them down the ICT, Dean Grossman, and executive also played key support roles in ensuring the stairs without their incubators. She leadership that the decision to evacuate that the operation went smoothly. Among was the first to do so. patients was the best course of action.” them were Emergency Management; Real One by one, the infants were covered At that point, the rapid discharge of Estate Development + Facilities; the Office with blankets and heating pads. Nurses remaining patients began. Members of the of Science and Research; Information and physicians held them snugly against ICT immediately notified the appropriate Technology; Security; Human Resources; the skin of their chests. All the while, they agencies, including the New York City Environmental Health and Safety; Building carefully squeezed bags of oxygen into the Fire Department and Office of Emergency Services; Supply Chain; the Division of babies’ lungs. Throughout the journey Management, that an evacuation was Animal Laboratory Resources; Facilities down nine flights of stairs—in some cases, imminent; called area hospitals to Operations; Patient Experience; Food with the baby’s mother accompanying the coordinate transfers; and visited clinical Services; and Therapeutic Recreation, team—the nurses would not take their eyes units throughout the Medical Center to Child Life, and Creative Arts Therapies. off the infants. “We were making sure that personally inform physicians and nurses In the ninth-floor NICU, as the day the breathing tube was in place and that the of the situation. For the most part, the nurses were briefing the night nurses baby was pink,” explains Margot Condon, evacuation was performed by hand— during a shift change, the unit went dark, RN, senior nurse clinician. If the baby’s many hands, in fact. Working in teams and the vitally important mechanical heart rate indicated that it was in distress, of six or more and assisted by members respirators and electronic monitors fell the team would pause until it stabilized. of the NYC Fire Department, caregivers silent. “Everybody ran to the babies to Once they reached the lobby, the nurses used “med sleds” designed for high-rise make sure they were fine,” recalls one and their tiny patients were transferred to evacuations to maneuver patients down nurse. “If you had a flashlight in your gurneys and whisked into waiting volunteer the dark, humid, twisting stairwells of phone, you held it right over the baby.” ambulances. They escorted the babies to Tisch Hospital and the Schwartz Health The four most critically ill infants, who their respective receiving hospitals, along Care Center with carefully choreographed couldn’t breathe on their own, relied on with their handwritten medical summaries, synchronization and tender loving care. oxygen from battery-powered respirators, to ensure continuity of care. NYU Langone’s medical staff was but the emergency batteries wouldn’t last About two hours later, power was concerned about the safety and well-being long. Menchu Sanchez, RN, senior nurse also lost in the 15th-floor CCCU. Achiau of all its patients, of course, but there clinician, who was caring for the sickest Ludomirsky, MD, the Andrall E. Pearson was particular concern for our pediatric baby in the unit, was quick to realize—and Professor of Pediatric Cardiology and chief

NYU Physician 4 WINTER 2012–2013 of the Division of Pediatric Cardiology, “I want to thank you for the extraordinary work a veteran of three wars, went from being battle ready to being triage oriented. “We you and the whole Medical Center team did brought the patient on a ventilator down to safely evacuate patients,” President Obama first,” he explained, “and the other five told them. “I hope you know how much the quickly followed. Within about 15 minutes, all six patients were brought safely down whole country appreciates what you’re doing.” 15 flights of stairs to the main lobby.” One of the biggest challenges, he recalls, was simply to keep opening the stairway door. “Because we were on a high floor,” he explains, “the wind in the stairwell was whipping so ferociously that it would take three of us just to push the door open.” Throughout the crisis, there were countless episodes of courage, compassion, and cleverness. With the subway system shut down, one attending physician hitched a ride on a Con Ed truck to get to the Medical Center, while another flagged down an NYPD patrol car. After many trips to and from higher floors of Tisch Hospital, one medical student was so visibly exhausted and dehydrated that a nurse insisted he drink a liter of sterile water. Even those most at risk showed grace under pressure. At one landing, a firefighter who was sweating profusely asked the patient he was helping carry how he was doing. “Me? I’m okay,” said the man with a Russian accent. “But you, I worry about.” By 11:00 a.m. on Tuesday, October 30, the last patient had been evacuated from NYU Langone Medical Center, and another kind of displacement—the Kimberly Glassman, PhD, RN, and Dean and CEO Robert I. Grossman, MD, removal of more than 15 million gallons used an iPhone to receive a call from the White House. of water—had already begun. About 24 hours later, amid the aftermath of the storm on Wednesday morning, Robert I. Obama told them. “I hope you know how construction of the Tisch elevator tower Grossman, MD, NYU Langone’s dean and much the whole country appreciates what and the new Emergency Department. CEO, and Kimberly Glassman, PhD, RN, you’re doing.” “This crisis has brought many losses vice president for patient care services Damage to the Medical Center was and many lessons,” Dean Grossman noted, and chief nursing officer, gathered in a costly and extensive, but there was a silver “but it has also highlighted what I will conference room to receive a scheduled lining. During the period when Tisch always remain thankful for, the dedication call from the White House (see photo). Hospital, the Emergency Department, of the entire NYU Langone community President Barack Obama, hearing of NYU and other facilities on campus have and our determination to prevail. I predict or i Donaghy Langone’s ordeal, wanted personally to been closed and without patients, NYU that we’ll look back on these difficult extend his praise and support. “I want Langone has been able to advance planned times with much-deserved pride, seeing to thank you for the extraordinary work improvements and new construction Hurricane Sandy as a turning point that you and the whole Medical Center team projects, including the installation of new ultimately propelled us to heights we

S L photograph did to safely evacuate patients,” President telephone and fire alarm systems, and the might never have reached otherwise.” •

NYU Physician WINTER 2012–2013 5

News from Medicine

Regional Differences Found in Imaging Use of advanced scans in prostate cancer is often inappropriate.

A little more than a year using the giant Surveillance, specific antigen (PSA) level ago Danil Makarov, MD, MHS, Epidemiology and End Results and Gleason score (a rating of Danil Makarov assistant professor of urology (SEER)-Medicare database from how mutated cells look under a and director of urological health the National Cancer Institute. microscope) are below certain services research, published a “We thought we would find ranges, then he’s considered low study showing that nationwide that certain regions adhered risk and doesn’t need testing about 34 percent of men with better to the guidelines beyond an annual biopsy. High- high-risk prostate cancer do not published by the National risk men should get a bone scan “No region really nailed it,” receive the imaging scans they Comprehensive Cancer and pelvic imaging, such as CT Dr. Makarov reports. “It doesn’t require, potentially delaying Network—that in some areas, or MRI, to see if the disease has appear that there’s a great deal their diagnosis and treatment they would do a great job of spread beyond the prostate gland. of discrimination going on to for more advanced disease. imaging high-risk patients and Dr. Makarov’s most recent ensure that the right person is The study, published in the not imaging low-risk patients,” findings appeared in the journal getting the right test at the right Journal of Urology, prompted Dr. Dr. Makarov says. Health Affairs last April. To his time. Some regions just like to Makarov to look more closely at If the tumor is entirely within surprise, he found that decisions use imaging, and some don’t.” the problem on a regional level, the prostate and a man’s prostate- about when and whether to In the wake of these findings, perform advanced imaging in he has received a $1.6 million, prostate cancer patients fall five-year career development prey to what he calls a regional award from the Department thermostat effect. In New Jersey, of Veterans Affairs to study for example, a large majority the factors that cause these of men—nearly 80 percent— thermostat variations in who need imaging get it. But imaging use and to develop about 65 percent of low-risk and test decision-making tools patients receive imaging that that can optimize such use in they don’t need, exposing them prostate cancer. to unnecessary radiation and “We’re trying to understand burdening the system with what drives these behaviors,” excess cost. In Utah, on the Dr. Makarov says. As the other hand, little more than government develops policies 20 percent of low-risk men get to ensure more appropriate use unneeded CTs and MRIs. But of costly medical technologies nearly half of high-risk Utah such as imaging, this is vital men who should have these information. “A bluntly scans do not. designed policy effort to decrease inappropriate use of imaging could also dial back appropriate imaging,” he says. “What’s needed is a policy A PSA-antibody test reveals to discourage inappropriate cancerous epithelial cells imaging and reward (red) in the prostate. Inc R esearchers, A bbey / P hoto Healthy tissue surrounds the appropriate imaging at the cancer (purple). same time.” • —Gina Shaw M i chael

NYU Physician illustrations by 6 WINTER 2012–2013 Leandro Castelao

Dafna Bar-Sagi

George Miller

Paying the Toll in Atsuo Ochi Pancreatic Cancer Studies show that toll-like receptors help fuel the cancer.

When pathologists examine and other invaders, and trigger and diminished a pancreatic tumor, they the body’s innate immune inflammation. These find relatively few cancer defenses. But in the presence of results, published in cells. Instead, fibroblasts and the pancreatic cancer cells, the October in Journal of infiltrating immune cells fill receptors actually promote the Clinical Investigation, led the mass. Equipped with cancer by sending inflammation the researchers to conclude special receptors, they engage into overdrive. that TLR7 is required for in a lethal cross talk with Interestingly, Dr. Miller’s progression of pancreatic pancreatic cells containing a studies have shown that TLRs cancer, and that TLR7 mutation in the KRAS oncogene. are scarce in normal pancreatic antagonists could prove to A colored scanning electron micrograph of a Chemotherapy can do little to cells, but human pancreatic be effective treatments for pancreatic cancer cell. stop the cancer, which usually cancer cells actively produce pancreatic cancer and chronic betrays few symptoms until it’s them, as do pancreatic cancer pancreatitis, for which there is relatively advanced, making it cells and the surrounding currently no effective treatment. one of the most deadly. inflamed tissue in mouse But Dr. Miller urges like pancreatitis,” Dr. Miller “Pancreatic cancer is the models. In his latest research, moving toward the clinic says. “But because of its quintessential example of an he and his colleagues Atsuo cautiously, because a similar complexity if you block one inflammatory cancer,” says Ochi, MD, assistant professor set of experiments in his lab, aspect of the signaling pathway, George Miller, MD, assistant of surgery, and Dafna Bar-Sagi, published last August in you can generate alternate professor of surgery and cell PhD, vice dean for science, Journal of Experimental Medicine, proinflammatory mechanisms biology. “But inflammation systematically worked out the provided a shocking result: that drive the cancer.” itself is a double-edged roles of TLR4 and TLR7, which Blocking TLR signaling through Fortuitously, TLR inhibitors sword. It can fight cancer or both contribute to the signaling a helper molecule called are being tested in human promote it, depending on the cascade leading to pancreatic MyD88 actually accelerated clinical trials for the treatment circumstances.” cancer growth. tumor growth. Further study of lupus, an autoimmune Dr. Miller, who received a Using a mouse model, implicated dendritic cells that disease characterized by generous grant from the Irma they showed that induced reside in the inflamed pancreas. inflammation. Those trials T. Hirschl Trust, focuses his TLR7 activation potently “Toll-like receptors may help prove Dr. Miller’s attention on toll-like receptors accelerated the development are central to driving the hypothesis that blocking (TLR), proteins that act as a sort of pancreatic cancer, while inflammatory component of TLRs could help dampen the of surveillance system on the uninduced animals had none the tumor microenvironment, inflammatory response in outside of immune cells such of the molecular markers of and blocking them can have pancreatitis and pancreatic as macrophages and dendritic cancer. Most important, adding very strong effects, slowing cancer, providing a glimmer of cells. TLRs ordinarily recognize a TLR7 antagonist prevented cancer development, even hope for patients who now have foreign proteins from bacteria this malignant progression in a premalignant condition few options. • —Karyn Hede esearchers, Inc R esearchers, S teve G sch m e i ssner / P hoto

NYU Physician WINTER 2012–2013 7

News from Medicine

Harvey Pass New Hope for Diagnosing Chandra Goparaju Mesothelioma Researchers find a promising candidate molecule for a blood-screening test.

For more than a decade, Phillips & Koningsberg, LLP, Harvey Pass, MD, the Stephen and the Simmons Mesothelioma E. Banner Professor of Foundation, has uncovered Thoracic Oncology, has been a number of promising searching for a biomarker for biomarkers, but all have mesothelioma, a particularly fallen short of being useful in virulent form of cancer that a screening test because they attacks the lining of the chest aren’t specific to mesothelioma. initial studies are validated, Dr. and lungs. Mesothelioma Even the protein osteopontin, Pass thinks a diagnostic blood patients have usually worked in discovered several years ago A colored scanning test could be developed in three industries like construction or by his team, was subsequently electron micrograph of years. Those with elevated levels asbestos, a fibrous mineral mining that expose them to high found in other kinds of cancer. once used widely in of fibulin-3 would undergo levels of asbestos. In October a team led by insulation and fireproofing. follow-up tests, including a CT Often taking decades to Dr. Pass reported on another Prolonged exposure to scan of the chest. high levels causes deadly develop, the disease is hard to biomarker that appears to rise mesothelioma. Another promising diagnose. Nearly 95 percent only in mesothelioma patients. biomarker was revealed in a of patients are diagnosed The finding, published in the study published last October in with late-stage disease and New England Journal of Medicine, in patients who had pleural PLOS: Dr. Pass and researchers typically survive less than a measured the expression of a mesothelioma but remained from SomaLogic, Inc., based in year; each year mesothelioma protein called fibulin-3 in the stable in individuals in the Boulder, Colorado, identified kills about 3,000 people in the blood of three different groups: other two groups. “It is present a set of 64 unique molecules United States. Dr. Pass, who is 92 patients with pleural in levels four to five times that together form a profile of vice chair of research for the mesothelioma; 136 individuals higher in the plasma of patients protein activity in the blood of Department of Cardiothoracic who had been exposed to with mesothelioma compared mesothelioma patients versus Surgery and division chief of asbestos but did not have with levels in asbestos-exposed those who did not have the general thoracic surgery, wants cancer; and 136 patients who patients or patients with disease. Follow-up studies will to improve this grim outlook by had not been diagnosed with several other conditions that refine the findings, Dr. Pass says. finding a biomarker that signals mesothelioma but who had cause tumors in the chest,” Dr. Even if fibulin-3 and the early-stage mesothelioma, when fluid in their lungs, an early Pass says. SomaLogic profile fall short of surgery, radiation therapy, symptom of mesothelioma and “It’s an exceptional being a screen for mesothelioma, chemotherapy, and new targeted several other conditions. molecule,” adds Chandra Dr. Pass will continue his therapies may help extend The results were significant. Goparaju, PhD, research research. “We have many patients’ lives. Although fibulin-3 levels scientist in the Department of options for discovering biomark- His research, supported in did not vary with age or sex, Cardiothoracic Surgery and one ers,” he says, “and we’ll keep part by Belluck & Fox, LLP, Levy they consistently increased of the study’s authors. If these looking.” • —Jane Bosveld esearchers, Inc R esearchers, A n d re w S yre / P hoto

NYU Physician illustrations by 8 WINTER 2012–2013 Leandro Castelao

The Synapse You Can’t Live Without

Decades of basic research yields insights Steven J. Burden published last August in Cell into delaying paralyzing disease. Reports provides proof of that concept. He and his team are Entranced with the junction “for everything that happens at now working to test potential between muscle and nerve, the neuromuscular synapse.” human therapies to boost MuSK Steven J. Burden began studying Without MuSK, there is to improve muscle function the neuromuscular synapse in no transmission between ALS. The nerves soon die, and and the quality of life of ALS the 1970s, when he was earning neurons and muscle cells. As no one has been able to find a patients. his PhD. This synapse allows a postdoctoral fellow, he began way of keeping them alive, Dr. “It’s a great delight to spend a neuron to pass a chemical studies that led to the discovery Burden says. Given no effective a career making basic discoveries, signal, acetylcholine, to muscle of Agrin, which is released from therapies, only two to three but there is also wonderful enjoy- and stimulate movement, neurons to stimulate MuSK, years commonly separate ALS ment applying this knowledge and it is the only synaptic and in 2008 he identified Lrp4 diagnosis and death. to treat diseases,” Dr. Burden connection required for as another master protein. Dr. Burden, however, believes says. “That is very, very survival. Neurons in the brain Most recently, in 2012, Dr. it is possible to rev up the gratifying.” • —Renee Twombly help us perceive the world, but Burden found that Lrp4 also activity of MuSK to keep the aren’t essential for survival, plays a crucial feedback role in nerve-muscle attachment viable he says. “Neuromuscular signaling from muscle to nerve. longer. In fact, a mouse study synapses, however, are crucial Simply stated, the trifecta of for breathing.” molecules works this way: On Today Dr. Burden, professor one side of the synapse, muscle of biochemistry and molecular cells express both MuSK and A light micrograph depicts pharmacology and cell biology Lrp4. On the other side, nerve neuromuscular synapses, the connections between and a member of the Skirball cells express and release Agrin. a motor neuron axon and Institute of Biomolecular The binding of Agrin to Lrp4 skeletal muscle fiber that it Medicine, is an internationally allows Lrp4 to turn on MuSK, controls. recognized expert in the which prepares the muscle workings of this fundamental to respond to acetylcholine. synapse. Over the years he has Then Lrp4 does a neat trick—it been methodically decoding signals back to the nerve to the interplay among three key ensure that neurotransmitter molecules that are critical to its release is efficient. health. Lately, his discoveries “You need all three of these offer potential strategies to molecules working in concert delay the devastating muscle for nerve stimulation of muscle,” wasting seen in amyotrophic Dr. Burden says. He also lateral sclerosis (ALS), also discovered a central fact: If this known as Lou Gehrig’s disease. dance is interrupted, nerves It has taken Dr. Burden decades disconnect from muscle— to reach a stage where his which is exactly what happens basic research offers clinical in ALS. The withdrawal of implications. motor nerve terminals from In 1993 Dr. Burden identified muscle, making the brain no a molecule, MuSK, which he longer able to control muscle describes as a master molecule movement, is the first sign of esearchers, Inc R esearchers, A str id & H anns-Fr i e d er M chler / P hoto

NYU Physician WINTER 2012–2013 9

Hitting the Bull’s-Eye in Prostate Cancer New Imaging Techniques Pioneered at NYU Langone Distinguish Deadly Lesions.

by Bryn Nelson • ILLUSTRATIONS BY STUART BRIers

magine a blindfolded archer taking aim at a bull’s-eye hung randomly in a room. A direct hit would be rare, even with 12 arrows in his quiver. For years, doctors have faced a similar challenge when using biopsy needles to probe the prostate gland in search of potentially lethal tumors. The walnut-size gland surrounding a man’s urethra is a hot spot for cancer, but notoriously difficult to access with existing imaging technology. As a result, the mostly blind biopsy technique that is still the standard of care often misses idangerous tumors while highlighting clinically insignificant ones. New MRI–based imaging methods pioneered by NYU Langone Medical Center researchers could offer clinicians some much-needed insight, potentially transforming how tumors are detected, diagnosed, and treated. “I’m very excited and believe we can correct all the woes of screening by integrating imaging,” says Samir Taneja, MD, the James M. and Janet Riha Neissa Professor of Urologic Oncology and professor of radiology. Prostate cancer, the second leading cause of cancer-related death among men in the United States, behind only lung cancer, struck nearly 242,000 men and killed more than 28,000 in 2012, the American Cancer Society estimates. Autopsies on men over the age of 50 who died from other causes have added a startling twist, however: nearly one-third showed early signs of prostate cancer. Scientists believe that most of these slow-growing tumors never become problematic during a man’s lifetime. But which ones might remain small and contained, and which ones could eventually become aggressive killers?

NYU Physician WINTER 2012–2013 11 Tissue biopsies have long been imperfect tools for spotting signs of trouble within the prostate. The the blood-based PSA prevailing technique of inserting a screening test is simple and dozen needles in a largely random inexpensive, allowing it to “tHere’s no douBt pattern throughout the gland may be widely used, the protein in my mind tHat reveal microscopic, nonlethal marker is not specifi c we HaVe to KeeP cancers that would never have for cancer. Several major sCreening, But we harmed the patient, contributing clinical studies, in fact, to over-detection. At the other have reached confl icting HaVe to sCreen extreme, the biopsies may completely conclusions about whether smarter.” miss a potentially lethal cancer, the test provides a signifi cant contributing to under-detection survival advantage. through false-negative results. “So The uncertainty led the even if the patient walks out with a U.S. Preventive Services Task negative biopsy, you’re never able to Force to issue a controversial comfortably tell him, ‘You don’t have recommendation last May cancer,’” Dr. Taneja says. against performing the PSA screen A biopsy can also underestimate for men in the general population. Taneja contend is almost certainly due the size and aggressiveness of a False-positive test results, the task in part to the widespread availability prostate tumor if the needle grazes force reasoned, often trigger an of early screening. the outside edge, leading clinicians equally unreliable biopsy, leading to “We’ve made progress. But if to erroneously recommend deferring over-diagnosis and overtreatment anyone thinks that we’ve optimized treatment in favor of regular of cancers that may never become screening by using a nonspecifi c monitoring, a strategy known as symptomatic. bleeding and infection marker and randomly placing 12 active surveillance. Herbert Lepor, can occur after a biopsy, and needles and taking 12 specimens, MD, the Martin Spatz Chair of incontinence and sexual impotency then he's naive,” Dr. Lepor says. Urology, says a recent analysis of his may result after a surgical or medical “There’s no doubt in my mind that extensive patient database—one of treatment, even with the care of we have to keep screening, but we the largest in the world—suggests the highly experienced and have to screen smarter.” Improved problem may be widespread. Since his skilled doctors. imaging, the researchers say, is the arrival at NYU Langone in 1993, Dr. Despite the risks, Dr. Taneja and best way forward because it will Lepor has performed thousands Dr. Lepor, whose research has been likely identify many of the aggressive of surgical prostatectomies to remove supported in part by the Joseph S. tumors often missed by random a malignant prostate gland after and Diane H. Steinberg Charitable biopsies in the past. “It will reduce digital rectal exams, PSA tests, Trust and NYU Langone Medical over-detection, do away with false- and standard biopsies suggested a Center Trustee Joel Smilow, are negatives, and potentially give us slow-growing cancer. Among his convinced that the PSA test has a more accurate depiction of that prostatectomy patients who might saved many lives; they say they are cancer,” Dr. Taneja notes. have been candidates for active “extremely disappointed” with the At NYU Langone, this ardently surveillance because of their biopsy task force’s recommendation. “I am sought goal could spring from a results, more than half actually a fi rm believer in prostate cancer technology called multiparametric had clinically signifi cant disease, screening,” says Dr. Lepor. “Turning MRI, developed by a collaborative according to pathology exams of their the clock back to prescreening would team of urologists, radiologists, and removed prostates. be absurd, based on what we know.” other researchers. “In one exam, A more general assessment of before doctors began embracing the patient is imaged with a variety cancer risk based on a prostate protein screening in the late ’80s and early of different MRI techniques that called prostate-specifi c antigen, or ’90s, he says, “the diagnosis of collectively let us better see tumors PSA, has also proved less than ideal. prostate cancer was pretty much and their location in the prostate, Unusually high PSA levels or a sudden a death sentence.” Since then, the and assess their biological potential spike in its production can sound mortality rate of prostate cancer has to cause harm,” says Andrew the alarm and suggest that a follow- dropped by more than 40 percent, Rosenkrantz, MD, assistant professor up biopsy is warranted. Although a dramatic decline that he and Dr. of radiology.

nYU PhYsician 12 WInter 2012–2013 One method, called a T2-weighted cancer antigen 3 gene, a cancer-specifi c image, produces an anatomical view probe that has shown early potential. of the prostate. Another, known as For men with positive MRI diffusion-weighted imaging, assesses test results highlighting an area the motion of water molecules of concern, subsequent biopsies within cells: the more restricted can become smarter too. NYU the movement of the molecules, the Langone is among the few medical denser the cells, and therefore the centers in the nation with access more likely that cancer is present. to a powerful navigational aid A third MRI–based measure, called called Artemis, a robotic system dynamic contrast enhancement, can that fuses MRI imaging results indicate the likelihood of cancer by with ultrasound technology. The assessing how blood is fl owing in resulting guidance system allows the prostate. Together, the data clinicians to aim biopsy needles signals are helping researchers with unprecedented precision distinguish between harmful and at areas of concern. The harmless tumors. computer software displays “tHis isn’t Just “We’re learning that the MRI is a three-dimensional view sometHing witH rather selective in that it typically of abnormalities on MRI Future Potential— identifi es cancers that are higher and marks those same sites grade and larger in size,” Dr. Taneja on an ultrasound image we’re using it day says. “So therefore, those are cancers of the prostate. Robotic in and day out now that would theoretically be lethal technology then directs the to HelP Patients.” for the patient.” In contrast, the biopsy needles to those spots researchers have detected clinically for the tissue sampling. signifi cant cancer in only about 5 “Now with imaging, we can percent of patients with negative MRI target not only the areas most results, suggesting that the technique likely to have a tumor but also the is missing relatively few cases. areas most likely to have aggressive based on the advanced imaging, Dr. tumors,” Dr. Rosenkrantz says. Rosenkrantz is helping to validate a And because ultrasound is much fi ve-point prostate cancer suspicion faster and more comfortable for the patients at NYU Langone are already score, similar to what oncologists patient, targeted biopsies based on benefi ting from the loosening have used for other cancers. A score the MRI–ultrasound fusion can be blindfold. Anyone with an abnormal of fi ve indicates that an abnormality performed in an offi ce setting. PSA test result is now examined is almost certainly cancer, while a The collaborators say initial with the advanced MRI technique to score of one strongly suggests that it results look promising, and several provide a clearer view of the prostate. is benign. team members are building their For now, all patients still undergo Within the next few years, the own software program to further a biopsy regardless of their MRI researchers hope to improve upon refi ne the process, while others results, but the arrival of the MRI– their initial results and confi rm are examining the technique’s cost ultrasound fusion method in 2012 preliminary data from other centers effectiveness. Despite the added has allowed the doctors to zero in on suggesting that a patient with a expense of multiparametric MRI regions of interest. In some cases, negative MRI result is highly unlikely imaging, Dr. Lepor and Dr. Taneja 4 guided needles have provided a to have clinically signifi cant disease. say the technology could actually better indication of the threat than the If a multicenter trial demonstrates save cost over time by decreasing typical 12 randomly placed ones, an that the results are reproducible, men unnecessary biopsies, surgeries, encouraging sign that the archers are with negative MRIs may eventually and other interventions. “I would zeroing in on the bull’s-eye. “I think be able to forgo biopsies altogether. venture to say that within two to we’re heading in the right direction,” Such patients might remain on a form three years, if all goes well, we’ll Dr. Rosenkrantz says. “This isn’t just of active surveillance, with doctors prove it, and it will change the way something with future potential— monitoring their levels of PSA or we screen men,” Dr. Taneja says. we’re using it day in and day out now other markers such as the prostate In many ways, prostate cancer to help patients.” •

nYU PhYsician WInter 2012–2013 13

e ruth About Lo ThAs testosteroneT replacement therapy grows more popular,w T debate rages over its safety and efficacy. How can patients and physicians sort out the science from the hype?

by Kenneth Miller • Illustration by Lonnie Busch obbie Donato, 54, woke up one morning with testicular A man can expect pain so severe that it sent him to the emergency room. his testosterone It didn’t occur to Donato that levels to decrease the event could be related to the bouts of fatigue and by about 1 percent impotence that had plagued a year starting in Rhim since his teens. But his doctor, Joseph Alukal, MD, assistant professor of urology and director of male his 30s. But by the reproductive health at NYU Langone Medical Center, discovered a condition that might have caused the patient’s time they turn 70, earlier problems as well as his more recent one: a varicose up to 50 percent vein in Donato’s testicles that kept his testosterone levels unusually low. of men have levels Rather than undergo surgery, which was not guaranteed below the normal to be effective in his case, Donato opted for testosterone replacement therapy, or TRT, an increasingly popular range for any age. treatment option for men with waning testosterone levels. Patients on TRT take regularly scheduled doses of artificial testosterone delivered through a variety of ways—injections, gels, patches, subcutaneous pellets, or buccal tablets attached to the gums. Donato opted for the gel, which quickly relieved his pain and restored his vigor. When its effect wore off after a couple of days, he tried between 2 million and 4 million men in the United States, injections but found that he disliked giving himself shots. most of them middle-aged or older. And a recent report by Finally, he turned to testosterone pellets embedded beneath the market research firm Global Industry Analysts, Inc., the skin of the buttocks. The insertion—performed in-office estimates that fewer than 12 percent of hypogonadal men under local anesthesia—was surprisingly easy, and the receive treatment for it. drug kept working for months. That troubles Dr. Alukal. Research over the past decade For the first time in recent memory, Donato was no has linked hypogonadism to decreased muscle mass and longer dependent on Viagra or Cialis. A creative director strength, decreased bone density, increased body fat, and a in a busy ad agency, he found he could work long days greater risk of type 2 diabetes and cardiovascular disease. without feeling utterly exhausted. Other men have not “The medical implications of this condition are real,” he been as fortunate. Although nearly half of men over age 50 says. “It’s not a negligible entity.” who have low testosterone notice nothing amiss, according The question is what to do about it. Annual to a 2007 study by the New England Research Institutes, prescriptions for TRT have more than doubled since a nonprofit public health research group, others may 2006, to 5.6 million, according to Bloomberg L.P., driven experience a vague constellation of ills including erectile by both the lengthening lifespans of American men and dysfunction, loss of libido, fatigue, insomnia, anxiety, their desire to remain active (sexually and otherwise) in depression, anemia, and impaired concentration. Yet their 50s, 60s, and beyond. A barrage of pharmaceutical they may ignore it, not realizing the symptoms indicate a commercials on TV urge men with a diminished appetite condition often referred to as andropause. for romance—or pickup basketball—to ask their doctors, “Is it low T?” Meanwhile, ads for testosterone-replacement Testosterone production naturally dips with age. clinics sprout up on the Internet like garden weeds. A man can expect his testosterone levels to decrease by But does testosterone therapy really work? More about 1 percent a year starting in his 30s. Some men important, is it safe? An increasingly loud chorus of continue to churn out enough of the hormone to father critics says the answer to both questions is no. “You’re a child well into old age. But by the time they turn 70, talking about worrisome potential toxicities with trivial according to the Baltimore Longitudinal Study of Aging, benefit,” says Nortin Hadler, MD, a professor of medicine up to 50 percent of men have levels below the normal at the University of North Carolina, Chapel Hill, and the range for any age. Studies suggest that hypogonadism— author of Rethinking Aging: Growing Old and Living Well in an the clinical term for testosterone deficiency—affects Overtreated Society. A review of 19 clinical trials in 2006,

NYU Physician 16 WINTER 2012–2013 he notes, found a higher rate of prostate cancer in men receiving TRT. A 2008 study in the Netherlands found Dr. Joseph Alukal explains some of the no improvement in strength, body fat, bone density, or medical implications of low testosterone to quality of life among 230 TRT recipients. A 2010 Boston a patient. University study was halted when elderly men receiving testosterone replacement developed heart problems at five times the rate of those taking placebos. Some physicians worry that TRT could eventually prove to be as dangerous as HRT—the hormone therapy given to millions of menopausal women before 2002, when it was found to

i ce d e gea beatr P hotograph raise the risk of heart disease, breast cancer, and stroke.

NYU Physician WINTER 2012–2013 17 In reality, diagnosing hypogonadism can be tricky even for a conscientious physician, and effective treatment may require far more than hormone therapy. To begin with, there's little consensus on what actually constitutes low testosterone.

Not everyone is convinced of TRT’s dangers, however. can do,” he says, “is educate people about the risks and Defenders counter that the negative studies were small, benefits and let them make a decision they’re comfortable short-lived, poorly designed, and, in some cases, statisti- with.” What worries him far more than the treatment cally flawed. “I think it’s a relatively safe drug,” says John itself, however, is the knowledge that men who don’t Morley, MD, director of the division of geriatric medicine really need testosterone supplements may be getting them at Saint Louis University School of Medicine. “I don’t from unscrupulous practitioners—or dosing themselves. think it should be given to every man who walks in say- All those ads, he believes, can stoke deep-seated male ing, ‘I’m feeling bad.’ But if you can show they’re hypo- insecurities about virility, sexual potency, and physical gonadal, it’s a very reasonable thing to do.” He points to a strength, prompting many men to wonder: Do I have 2009 research review that he coauthored in the journal enough testosterone? If those men go online to research Therapeutics and Risk Management, which concluded that the symptoms of low testosterone, they’re likely to run TRT may improve “libido, sexual function, bone density, across the standard 10-point ADAM questionnaire muscle mass, body composition, mood, erythropoiesis (the acronym stands for Androgen Deficiency in Aging [red blood cell production], cognition, quality of life, and Males). This quiz, designed to help doctors make an cardiovascular disease.” initial screening, inquires not only about the strength Yet even physicians who routinely prescribe testoster- of the subject’s erections and libido, but also his overall one therapy concede that the supporting data are inconclu- mood and energy level: “Are you sad or grumpy? Have sive; so far, no one has completed a large, long-term study you noticed a recent deterioration in your ability to play that could settle the debate. And while they may discount sports?” If the answer is yes to at least one of the sex- reports of cardiac complications, they acknowledge that related questions or three of the others, a physician may TRT can have unwelcome side effects. Because the brain advise a testosterone test; in most cases, the results will be signals the testicles to stop producing testosterone in re- normal. But a middle-aged Web surfer might mistake his sponse to TRT, prolonged use may lead to permanent infer- answers for a diagnosis and then go off in search of a cure. tility. Other potential problems include polycythemia, or “A lot of men out there are convinced that they have overproduction of red blood cells (which can lead to stroke), low testosterone,” says Dr. Alukal, “and a massive and sleep apnea (which can lead to insulin resistance and industry has sprung up to take advantage of them.” Some high blood pressure). Although there’s no evidence that testosterone clinics, he observes, are willing to treat testosterone replacement causes prostate cancer, it may virtually any paying customer. Men who would rather accelerate a previously undetected one. A responsible bypass the doctor entirely (and the black-market) can doctor will warn patients of the possible dangers, check legally purchase nutritional supplements, such as DHEA, their prostates and their PSA counts before beginning which is converted to testosterone in the body. Although treatment, advise them to bank a sperm sample if they often labeled as “natural,” such products can have side hope to conceive children, and then monitor them regu- effects similar to those of testosterone-replacement drugs— larly for signs of trouble. potentially disastrous without proper medical supervision.

Given all the uncertainties, Dr. Alukal (an In reality, diagnosing hypogonadism can be tricky andrologist as well as a urologist) is reluctant to endorse even for a conscientious physician, and effective TRT carte blanche for his hypogonadal patients. “All I treatment may require far more than hormone therapy.

NYU Physician 18 WINTER 2012–2013 To begin with, there’s little consensus on what actually constitutes low testosterone. The most common test assays the total amount of testosterone in a patient’s blood. But while the Endocrine Society defines the normal level as a measurement between 300 and 1,000 nanograms per deciliter (measured in the morning, when levels are highest), reputable labs may set the limit as low as 240 ng/ dl, depending on their own calibrations. “If it’s a lab that knows what it’s doing,” Dr. Alukal says, “I’ll generally go with their number.” But testosterone levels tell only part of the story. As men age, increasing amounts of testosterone are bound to a protein known as sex hormone binding globulin (SHBG) and can no longer be absorbed by the body’s tissues. For that reason, Dr. Alukal also orders assays for “free testosterone,” the portion not bound to SHBG. An older patient may have a low free-testosterone count, even if his total testosterone registers as normal. Hypogonadism is especially easy to miss in men under the age of 40. “Most of them have no primary physician,” Dr. Alukal says. “There’s no demographic that utilizes healthcare resources less than guys between 18 and 35.” Men in this age group typically show up in his office because they’re suffering from erectile dysfunction or find themselves unable to conceive a child. A small number prove to have abnormally low testosterone levels. (Because TRT itself can cause infertility, Dr. Alukal prescribes a different treatment for patients who are trying to conceive—perhaps clomiphene, which boosts the body’s own testosterone production, or anastrozole, which prevents the breakdown of testosterone already in circulation.) Of course, a testosterone deficiency could also indicate Men with low testosterone are often referred to a serious underlying condition. There are two main cardiologist Howard Weintraub, MD. varieties of hypogonadism: primary (originating in the gonads) and secondary (originating in the endocrine system). The disorder may be congenital or acquired and can result from a wide variety of causes: damage to which is why erectile dysfunction can be a harbinger of the testicles; chronic illnesses such as diabetes, obesity, heart disease. Some studies indicate that testosterone or liver disease; a malfunctioning pituitary gland or supplementation improves vasodilation. But additional hypothalamus; a genetic condition such as Kallmann measures may be needed to repair existing cardiovascular syndrome; radiation or chemotherapy for cancer; or the damage and to prevent further deterioration. side effects of various medications. Another key to heart health, of course, is regular exercise—and by improving a patient’s mood and energy Before deciding on a course of treatment for a patient level, TRT can make getting off the couch less daunting. with low testosterone, Dr. Alukal often collaborates “I’ve had guys come back to me and say, ‘I’ve needed this with other specialists, such as cardiologist Howard stuff for a long time. I just didn’t realize it until I was on it,’” Weintraub, MD, clinical director of the Center for the Dr. Alukal says. Prevention of Cardiovascular Disease. “Low testosterone One such patient is Robbie Donato. “I’m doing great,” he is a risk factor for cardiac disease for the same reason says. “I feel like I’m back to my old self again.” that high cholesterol, hypertension, or diabetes are,” That’s just the kind of result that Dr. Alukal hopes for. Dr. Weintraub explains. All these conditions impair “Testosterone replacement doesn’t work for everybody,” vasodilation, the ability of the blood vessels to relax and he says, “but when it does, it can make a remarkable photograph R ene P erez photograph allow increased flow. Vasodilation also enables erections, difference in a man’s life.” •

NYU Physician WINTER 2012–2013 19 4041

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54 55 56 5258 59 60 57The Risks of Fathering61 62a Child Later64 in Life A gROWINg BODY OF RESEARCH65 INDICATES THAT CERTAIN BRAIN DISORDERS IN CHILDREN ARE RELATED TO THEIR FATHER’S AgE.

6968 BY karen hoPkin63 and aUBin tYler • illUstration BY keith negleY

nYU PhYsician 20 WInter 2012–2013

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51 division increasing the likelihood of error. The researchers knew that the idea of a ticking male biological clock was not new. A century ago, an observant 45 49 obstetrician named Wilhelm Weinberg noted that of the 53 50 thousands of babies he had delivered in Stuttgart, germany, the later-born children were more frequently affl icted with certain disorders—including achondroplasia, a form of 55 54 56 dwarfi sm—than their fi rst-born siblings. Weinberg ascribed as a YoUNg cLiNicaL research fellow at Columbia this enhanced susceptibility to the advanced age of the University in the early 1990s, Dolores Malaspina, MD, parents. Decades later, pioneering British geneticist L. S. began searching for a genetic link60 in families with Penrose conducted additional statistical analyses that pointed 58schizophrenia, an illness that had blighted a promising specifi cally toward the age of the father, not the mother, as 52 future59 for her younger sister, Eileen. To her surprise, she the culprit. In 1947 the brilliant population geneticist J. B. S. simply could not fi nd enough subjects with a relevant family Haldane speculated that sporadic cases of hemophilia that history. “Everyone talks about61 schizophrenia being a genetic didn’t conform to known patterns of inheritance could be due 57 64 disease, but the vast majority of people with schizophrenia to errors induced during sperm cell division. 62 have no family history,” she says. How could schizophrenia65 persist if not through heredity? Science has long known that the illness tends to run in families. The risk of developing schizophrenia jumps from 1 percent among the general population to 10 percent if “ In evolution, genetic diversity is 63a primary family member, such as a sibling or parent, is affected. but conventional inheritance seemed to solve only a advantageous. So mutations in small piece of the puzzle. “Seeing the struggles of people like older men may be a way of saying, my sister, I felt there had to be better answers,” she says. Dr. Malaspina, now the Anita Steckler and Joseph ‘Okay, let’s have some variety.’” Steckler Professor of Psychiatry and director of the Institute for Social and Psychiatric Initiatives at NYU Langone Medical Center, resolved to fi nd them. In 2000 she teamed up with epidemiologist Susan Harlap, MD, research professor of psychiatry, obstetrics/gynecology, Yet the theory that Dr. Malaspina and Dr. Harlap put and environmental medicine, to analyze data from the forth was met with great skepticism. “Many thought it was Jerusalem Perinatal Study, a massive health survey based something about men who married later who may have had on 92,408 babies born in Jerusalem between 1964 and some constitutional problem, such as shyness or a social 1976 and followed into adulthood, along with 83,000 disability,” Dr. Malaspina recalls. parents. When the researchers anonymously matched These doubts began to shrink, however, as the records of individuals who were eventually diagnosed with epidemiological evidence grew. In 2006 Dr. Malaspina schizophrenia, they discovered a startling trend: The risk collaborated with other researchers to study the Israeli data of developing schizophrenia increased steadily with the and discovered another brain disorder correlated with older age of the father. It doubled among offspring whose fathers fathers: autism. Their analysis found that men in their 40s were 40 years old when they were born and tripled in those were six times more likely to have children with autism than whose fathers were older than 45. those under 30; for men over 50, the risk was ninefold. The Publishing their results in the Archives of General Psychiatry, risk rose steadily as fathers aged, a characteristic pattern of Dr. Malaspina and Dr. Harlap theorized that the passage de novo mutations. of years increased the number of spontaneous, or de novo, More recently, a rush of papers has offered compelling mutations passed along to offspring via the fathers’ sperm. proof of a paternal link at the genetic level. Last spring three Unlike women, who possess their full complement of eggs separate groups from Yale, Harvard, and the University at birth, men make sperm throughout life, a process that of Washington published analyses of sequencing data on becomes more error prone as men age. Males, from the time nearly 600 families with autism spectrum disorder in the they reach puberty at 13 or 14, make sperm every 16 days journal Nature. Each team found de novo (spontaneous) or so. by age 20, a man’s spermatogonia, the stem cells that mutations in the exome, a region of the genome thought give rise to sperm, have divided more than 150 times; by age to code for most human diseases. In the University of 50, those cells have divided more than 850 times, with each Washington study, for example, researchers sequenced

nYU PhYsician 22 WInter 2012–2013 long strands of DNA containing more than 100 base pairs accumulate, causing birth defects. from both parents and affected offspring and were able Why would evolution preserve such a destructive to determine, in about a fifth of cases, which parent had mechanism? Paradoxically, notes Dr. Harlap, the mutations contributed the DNA containing the new mutations in the in FGFR may confer an advantage to precursor sperm, child. The rate of new mutations from fathers, they found, helping them divide more efficiently and outcompete was about four times that of mothers. And in all three their neighbors, just as they do in cancer. In the testis, studies, the mutation rate rose with advanced paternal age. this phenomenon has been called the “selfish sperm” Another major paper followed in August, when Icelandic hypothesis. Nature’s effort to introduce variability into researchers announced in Nature that they had sequenced the gene pool occasionally and tragically produces human the entire genome of 78 families with either autism or disease as well. “We don’t know that all progeny are schizophrenia and found, again, that fathers were the disadvantaged by mutations, though those with autism dominant source of new mutations in offspring. Moreover, certainly are,” Dr. Harlap adds. “In evolution, genetic those mutations doubled every 16.5 years, increasing eightfold diversity is advantageous. So mutations in older men may in 50 years. In an accompanying editorial, University of be nature’s way of saying, ‘OK, let’s have some variety.’” Michigan geneticist Alexey Kondrashov, PhD, noted that Dr. Malaspina is quick to point out that the science does not if a 20-year-old father’s contribution is 25 mutations, a suggest older men should forgo having children. “Most of the 40-year-old father transmits about 65, whereas the mother’s time, the child will not have one of these disorders, so I don’t contribution remains at about 15, regardless of her age. think the data should suggest men not have children at a Spontaneous mutations are “some of the most interesting later age,” she says. But they do point to the need to rethink variants in the whole of genetics,” says Yale University’s paternal health. “Before, we thought that sperm was not Stephan Sanders, MD, lead author of one of the papers. “How really dependent on the lifestyle of the man,” she says. “Now else do you explain a child who has a disorder and parents we have to say that it’s important.” who don’t?” He estimates that spontaneous mutations Above all, the researchers are hopeful that the windfall account for about 20 percent of autism cases, a figure in of data will lead to new diagnostics and therapies. “My own accord with Dr. Malaspina’s own estimates for both autism interest in all of this work is that it will change treatment,” and schizophrenia. Of the 20,000 genes in the entire genome, says Dr. Malaspina. “That’s what I’m hoping to get to: about 1,000, or 1 in 20, may contribute to autism. treatment, prevention, and cure.”• Triggers in the environment like pollution, stress, and diet can also induce heritable genetic changes by turning genes on and off and ultimately changing how they function, a phenomenon known as epigenetics. But paternal age is the dominant risk factor for spontaneous mutations. “It’s incontrovertible that new mutations arise largely based on paternal age,” Dr. Malaspina says. With more evidence than ever before that mutations associated with paternal age underlie many cases of autism and schizophrenia, Dr. Malaspina and Dr. Harlap have now turned their attention to the question of which genes—and more specifically, which mutations within those genes— actually cause disease. In collaboration with geneticist Mary- Claire King, PhD, at the University of Washington, they have sequenced the coding region of genes in a dozen patients with schizophrenia and their parents. “The work is still in progress, but we’ve already found four new point mutations in an exciting set of novel genes,” Dr. Malaspina says. These novel genes code for proteins that are found in some of the same cellular pathways associated with fibroblast growth factor receptor (FGFR) genes. Many of the other conditions related to paternal aging are caused by mutations in FGFR genes, Dr. Harlap explains. Moreover, certain point mutations in the genes result in more active Dr. Susan Harlap (left) and Dr. Dolores Malaspina and their collaborators are now searching for specific protein as people age, contributing to many kinds of cancer. mutations associated with paternal aging that are

photograph S asha Ni alla photograph And, as men age, point mutations in testicular germ cells can passed along to offspring via the fathers’ sperm.

NYU Physician WINTER 2012–2013 23 The Melody of

Finches

A neuroscientist learns how zebra finches perfect their love song and, in the process, makes some surprising discoveries about how neurons hook up.

By Jim Schnabel photograph by Gloria Baker

24 Michael Long, PhD, studies the love song of Australian zebra finches to understand the basic neural logic of complex learned behaviors.

25 ustralian zebra finches After earning his PhD in neuroscience at Brown are popular pets that usually University in 2003, Dr. Long moved to Cambridge, nestle together amiably on Massachusetts, to become a postdoc in the laboratory of their perch or on the floor of MIT neuroscientist Michale Fee, PhD. They developed a their cage picking at seeds. miniature thermoelectric device that can cool tiny patches Orange patches flanking bold of the brain and used it to find the special spot that streaks of white and black on controls zebra finch song timing. When this spot, known their faces make them easy as the HVC (high vocal center) nucleus, was cooled, the Ato identify, and they aren’t especially noisy. But when the birds’ song slowed unmistakably. Scientists had known time comes for courting, these small, dusty gray birds let that multiple brain regions are involved in producing the out a song that has all the allure of a wheezing rubber duck. zebra finch song, but they didn’t know whether all, some, Amazingly, this repetitive, brraapping sound romances a or just one controlled the timing of the song’s individual female finch. sound bursts. “We showed that all the timing control is This raucous love song fascinates Michael A. Long, PhD, localized to this single nucleus of about 40,000 neurons,” assistant professor of physiology and neuroscience and Dr. Long says. otolaryngology, because it is a complex learned behavior— Nature published the finding in 2008, and soon after, mastering the precise melody with which to woo their Dr. Long joined the NYU School of Medicine. Today avian mates takes considerable practice. hundreds of twittering zebra finches fill his laboratory’s “We know surprisingly little about the neural aviary. His chief aim is to determine how the neurons underpinnings of such behaviors, despite their fundamental in the zebra finch’s HVC hook up to produce the precise importance in our lives,” Dr. Long says. “The finch’s love sequence of brraapps and squeaks in a love song. “You song is a very good model for a complex learned behavior.” can’t understand this by looking at the firing rate of an A young male zebra finch spends several months individual HVC neuron,” Dr. Long says. “You have to look learning the song from his father, and during this period at multiple neurons and see how they work together.” will practice it several hundred thousand times. “The bird To do this, he has invented a miniature microdrive half spends all day practicing this skill, just like a violinist or the weight of a penny that can be fastened to the bird’s a tennis player must practice all day,” Dr. Long says. The head. Linked to specialized electronics by a short tether, it resulting song varies widely from one bird to another but lowers a minuscule electrode into the finch’s HVC, which an individual reproduces it in an almost identical way each lies close to the surface of the brain, and positions the time—hundreds of times a day if a potential mate appears. electrode within a single neuron at a precise depth. Then Birds that fail to learn this special song produce a plaintive the electrode (one-thousandth the thickness of a human screech that leaves female finches cold, the songbird hair) measures how the voltage in that neuron changes equivalent of leaving the bar alone. How the bird’s brain while the bird sings. cells wire themselves to produce this song is still a mystery, Using this device to record from individual brain cells but it could be the key to understanding the mechanics of as the finch serenades his beloved, Dr. Long has amassed learned behavior generally. strong evidence, described in Nature in 2010, of the basic Since the 1960s dozens of laboratories have studied the principles by which HVC song neurons are organized. brains of zebra finches for clues to how birds in general learn The HVC, he says, is like a choir: Each member to sing—and by analogy, how humans learn speech and ultimately commands a specific set of vocal muscles to other complex skills. But Dr. Long, who was recently named work at a specific time and in a specific way. However, in a Robertson Neuroscience Investigator by the New York a human choir, each member can hear all the others and Stem Cell Foundation and whose research is also supported can watch a choirmaster to know when and what to sing. in part by the Rita Allen Foundation and The Esther A. The HVC isn’t necessarily wired that way. Dr. Long has & Joseph Klingenstein Foundation, isn’t interested in the found evidence that it has a more linear organization, a detailed workings of birdsong related to any specific animal synaptic chain in which each participant plays its own or human skill; he wants to understand the basic neural short, 10-millisecond interval of sounds, which cues the logic of all learned behaviors—in other words, the rules by next player—and so on down the chain, for roughly 100 which neurons organize themselves to command precise distinct intervals. Each “player” is a group of about 200 sets of muscles in precise sequences. neurons (only 20,000 HVC neurons actually fire during “The finch is not the only game in town,” Dr. Long a song), and these groups appear to have enough internal says, “but I think it’s the best for studying a manageable redundancy to withstand minor losses without fumbling number of neurons that produce a clearly learned the tune—as one might expect, given the evolutionary

complex behavior.” consequences of failing to produce the correct song. i on by lucy rea di ng Illustrat

NYU Physician 26 WINTER 2012–2013 Dr. Long’s combination of associated with movement, speech, and other functions. Neurosurgeons now identify such tissue with electrodes, ambitious neuroscience which emit a weak current, in order to avoid removing the tissue during surgery. But the electrodes themselves can with roll-up-your-sleeves trigger seizures. Dr. Long’s cooling device may be safer, engineering is influencing because it suppresses neuron excitability, marking surgical no-go areas, for example, with striking slowdowns in a research well beyond his patient’s speech. laboratory. The microdrive that Dr. Long uses on his zebra finches also has potential outside his own lab. Because it enables scientists to record from single neurons throughout the brain’s various processing centers, it can be used in a variety of lab animals, not just in singing birds. For Dr. Long now plans to build a functional map of this example, “We are planning to use Dr. Long’s microdrive HVC choir, at least for a meaningful segment of the and other methods on mice to understand memory zebra finch song, to study how it changes throughout the organization in the hippocampus,” says György Buzsáki, learning process. His graduate students Daniel Okobi MD, PhD, the Biggs Professor of Neuroscience at NYU and Sam Benezra are now training zebra finch males Langone Medical Center. to sing while their heads are fixed beneath a large two- Tools such as the microdrive may also contribute to photon microscope. They expect to use the sophisticated understanding how brain networks are organized, one of microscope, which can peer deep into living brain tissue, to the most pressing questions in the field of neuroscience. visualize and precisely time the activities of HVC neurons “We already know a lot about what genes do and what in one small part of the nucleus, then another, until single cells do, but it’s such a difficult problem to see how they have data for a sufficiently large area. Postdoctoral large groups of cells function together,” Dr. Long says. researcher Daniela Vallentin, PhD, has also been refining “Cells work as a society, and you can’t understand a society the head-mounted microdrive device to enable longer and just by studying individuals—that takes you only so far.” • longer recordings from a given neuron. Her maximum single-neuron recording time in a finch brain so far is nearly four hours. In the finch brain, song is controlled by the high vocal Dr. Long’s combination of ambitious neuroscience center (HVC). A microdrive that measures the activity of neurons in the birds reveals that each group of these with roll-up-your-sleeves engineering is influencing neurons is active for about 10 milliseconds during the research well beyond his laboratory. For example, song. Each group is likely connected to the next, like neurosurgeons at the University of Iowa are testing his links in a chain, for sequential intervals. Each link signals downstream motor neurons (RA, robust nucleus of miniature cooling device on patients who are about to the arcopallium) that ultimately drive the vocal and undergo epilepsy surgery to identify tissue in the brain respiratory muscles to produce the song.

A B Microdrive 10 millisecond 10 millisecond Electrode interval in final song interval in final song

Group 1 HVC signals to RA

Song production pathway to vocal RA muscles

Group 2 Distinct group of signals to RA neurons in HVC

nxll

10 milliseconds Time

27 faculty conversation Combating a Devastating Infection A physician-scientist has devoted his life’s work to understanding the notorious bacterium Staphylococcus aureus. By Claudia Kalb

Staphylococcus aureus infects some 1.2 million patients in hospitals each year. Notorious for causing a host of devastating infections from skin boils to toxic shock syndrome and for being especially difficult to treat, it has developed resistance to the most powerful antibiotics, including vancomycin, the drug of last resort. Richard Novick, MD (’59), the Recanati Family Professor of Science and a member of the Skirball Institute of Biomolecular Medicine, has dedicated his career to analyzing and combating the bacterium. His first major contribution to the field came in the early 1960s, when he found that a circular strand of DNA called a plasmid carried a staph gene responsible for antibiotic resistance. Dr. Novick’s discovery, along with others at the time, revolutionized scientists’ understanding of how bacteria manage their genes. He served on the faculty of Yale University, the National Institute for Medical Research in London, Vanderbilt University, Rockefeller University, Columbia University, and the Public Health Research Institute, and returned to NYU School of Medicine in 1993. He was elected to the National Academy of Sciences in 2006. The exploitation of science, including the misuse of antibiotics, especially in animal feed, has concerned Dr. Novick throughout his career, and he is outspoken about his opposition to the development of biological weapons. An intrepid outdoorsman, Dr. Novick bikes to his lab from his Upper West Side apartment; he also hikes the Appalachian Trail as well as more demanding terrain in the Alps and Himalayas. On weekends at his home in Kent, Connecticut, Dr. Novick hunts for mushrooms and crafts bowls and Dr. Richard Novick vases out of wood.

NYU Physician photograph by 28 WINTER 2012–2013 Gloria Baker When did you become interested in studying Staph? “For young scientists, I’d say study what I took a year out of medical training to do a mini PhD in Werner Maas’s lab, working on the great scientists have done. Learn about E. coli gene regulation. That got me interested the world, look at history, look around you.” in bacterial biology and genetics. My interest in Staph started during my postdoc in London with Martin Pollock. I spent the first year or two trying to see if we could get mutant varieties of infections by inhibiting the expression of Our favorite is probably the black trumpet, Staph to attack methicillin, the new wonder drug. virulence genes. We discovered an inhibitory Craterellus cornucopioides. It was a rather dubious enterprise and it failed, peptide that does just that to block a but my research led to the discovery of the first staphylococcal infection. We’re working out When did you learn to work with wood? plasmid found in Staphylococcus and I have stuck the details of that strategy, which, although It goes back 20 years and involves mostly wood with staphylococcal research ever since. it is effective in animal models, has yet to turning, using a lathe. Although I love the idea be tried in humans. We’re also trying to of doing sculpture, I’m completely incompetent Staph can inhabit our bodies without harm, but it do something to interfere with biofilms, when it comes to doing anything freehand. If it’s can also cause deadly infections. How can it be so aggregations of bacteria and other organisms constricted to something round, I can handle it. benign and so toxic? that attach to surfaces and are largely That’s the $64 billion question. Thirty percent impermeable to antibiotics: Staph biofilms What worries you most about medicine and of people carry Staph, primarily in the nose, are a big problem in surgical implants for science today? where it resides without penetrating the nasal this very reason. I’m also working on an One of my big concerns is the way medical care tissues, raising two big questions: When the antistaphylococcal vaccine, the basis of which is being done. First, medicine should not be organism is living in the nose, does it interact is top secret for the moment. for profit. Period. Medicine for profit has been with the immune system? Are the genes that nothing but a disaster in every respect. Second, cause infection being expressed? I think these How would you define the path of your career? medicine should not be run by insurance questions are very well worth looking into. I have to confess, I’m largely an opportunist in companies. These two aspects of medicine as science. Some scientists might set out to answer practiced in the United States have led to a god- You have a collection of close to 12,000 Staph a certain question and devote their entire lives awful mess. I’m an environmentalist and I think strains. How did you acquire them and what to it. Good examples would be Fred Sanger, humans are overrunning the planet in ways distinguishes one from another? who set out to determine the sequences of that are destructive long-term. Fisheries are We started collecting them when I was in nucleic acids, and John Kendrew, who wanted being depleted. Fossil fuels are being exploited, England in the 1960s. Many are clinical isolates, to know the structure of a protein. I never did the planet is heating up. I’m terrified about obtained from patients. The others are research that. I fell into Staphylococcus, because during what’s going to happen, because commercial strains, which we’ve constructed by changing, my postdoc in London, I was asked to work interests are very rich and powerful, and very adding, and subtracting genes. We’re trying to on a problem of antibiotic resistance in Staph. shortsighted. answer questions about how the bacteria are Another case is toxic shock syndrome, caused organized and how they regulate and transfer by a staphylococcal toxin known as TSST-1. What are you most optimistic about? their genes. We were invited by Procter & Gamble to clone I certainly have a lot of hope for medical the TSST-1 gene, which led us to a new class of progress and for the success of science in solving Do you believe it will ever be possible to develop an mobile genetic elements based on their carriage problems. I’m excited about that. After all, that’s effective antibiotic against this highly resistant bug? of this gene. That discovery has ballooned into a what I do as a lifework. Absolutely. We’re working on one. In the late really cool project. That’s the way it has always ’80s, we cloned the gene for lysostaphin, an happened in my career. Where should young scientists look for inspiration? enzyme that dissolves Staphylococcus. Lots of Where do you look for inspiration? people have studied it and shown that it is When did you start hunting for mushrooms and I used to look for it through historical insights. absolutely unparalleled for wiping out Staph what’s your favorite variety? At the moment, my inspirations are generated in infected animals. A company we founded to It started in England. I noticed a big white internally. I’ve been around long enough. produce it for clinical applications didn’t work puffball on the lawn where we were working. For young scientists, I’d say study what the out. Now we’re again trying to find an angle to I knew it was edible—I don’t know how—so I great scientists have done. Learn about the make it commercially viable. picked and ate it and it was pretty good. My world, look at history, look around you. Look wife and I have eaten 30 species or more, but at some phenomenon that everyone takes for What other approaches are you taking? she’s gotten fussy lately. She’ll only eat three granted and nobody knows about and ask, There’s been a lot of interest in treating bacterial or four of the most highly regarded species. “What is that all about?” •

NYU Physician WINTER 2012–2013 29 FACULTY NEWS

Honoring Three Masters and a Major Benefactor on DEAN’S HONORS DAY

NYU SCHOOL OF MEDICINE’s 11th annual Dean’s Honors Day was held on Tuesday, October 2, 2012, at Farkas Auditorium to honor achievement, commemorate accomplishment, and celebrate excellence with the granting of tenures, promotions, chair appointments, and other distinctions to worthy faculty members and others. The NYU Brass Quintet opened the event and Dean Robert I. Grossman, MD, led a platform that included Kenneth Langone, chairman of the board of trustees, NYU Langone Medical Center; John Sexton, PhD, JD, president, New York University; and Steven B. Abramson, MD, vice dean for education, faculty and academic affairs. Three distinguished faculty received the honor of the highest-profile awards: Master Clinician, Master Educator, and Master Researcher. “The three people honored this year have woven together powerful intellect, sustained effort, steadfast achievement, and greatness of spirit,” Dean Grossman said. “They remind us that excellence is an instantly recognizable absolute and, Clockwise from top left: Philip K. Moskowitz, MD, Danny Reinberg, PhD, at the same time, a deeply individual Dr. Grossman and Larry A. Silverstein, and Linda R. Tewksbury, MD. achievement. They shine in very different but equally spectacular ways.” Philip K. Moskowitz, MD, the and board chair of the Cancer Institute at protein production. Most significantly, he Mamdouha S. Bobst Associate Professor the Medical Center, and her husband Larry has identified some of the key enzymes that of Internal Medicine, was named Master Fink, also a trustee, recently endowed The control access to DNA in its cellular form, Clinician. Dean Grossman lauded Dr. Philip K. Moskowitz, MD, Professor and where it is curled tightly around proteins Moskowitz for “embodying all the caring, Chair of the Department of Neurology. called histones. Among his laboratory’s skill, and expertise that would define Steven L. Galetta, MD, was named to the major breakthroughs was the development such recognition,” characterizing him as endowed chair. of a powerful new methodology for an outstanding clinician and dedicated Danny Reinberg, PhD, professor of studying the unwinding of DNA required teacher and calling him a “doctor’s doctor” biochemistry and molecular pharmacology for gene activation. This finding, based on who has been “a pillar of NYU Langone and a Howard Hughes Medical Institute seven years of research, allows scientists to Medical Center for nearly 50 years.” A investigator, received the Master Scientist investigate the discrete steps necessary to member of the executive committee for Award. A National Institutes of Health turn genes on and off at the proper time and medical school admissions, Dr. Moskowitz Merit Award recipient, Dr. Reinberg and in the proper place. Dr. Reinberg is a co- directed the House Staff Teaching Program his collaborators have made fundamental founder of Constellation Pharmaceuticals, a for 15 years and has been faculty director of discoveries in gene transcription and the chromatin therapeutics company, based in development for the past decade. Lori Fink, mechanism by which information from Cambridge, Massachusetts. a trustee of NYU Langone Medical Center DNA is transferred to the RNA that directs Linda R. Tewksbury, MD (’90), assistant

NYU Physician 30 WINTER 2012–2013 professor of pediatrics and an influential Dr. Tsien Receives advocate for scholarship in medical education, received the award for Master Neuroscience Award Educator and Mentor. “Mentors shape lives, RICHARD W. TSIEN, DPHIL, not just career choices,” Dean Grossman Druckenmiller Professor of Neuroscience, said. “And in so doing, they also make chair of the Department of Physiology lasting contributions to the quality and and Neuroscience, and director of effectiveness of our entire profession.” the Neuroscience Institute at NYU Dr. Tewksbury coordinates the advisory Langone Medical Center, received the program for pediatric program applicants Julius Axelrod Prize from the Society and was among the first cohort of 10 Master for Neuroscience during its annual Scholars Advisors chosen for the School's meeting. The prize recognizes exceptional advisory program. The graduating class of Dr. Littman Elected to achievement in neuropharmacology or 2011 elected her Distinguished Teacher in Institute of Medicine a related field and exemplary efforts in the Clinical Sciences. mentoring young scientists. It is supported Larry A. Silverstein accepted the Dan Littman, MD, PhD, by the Eli Lilly and Company Foundation 2012 Valentine Mott Founders Award in the Helen L. and Martin S. and includes a $25,000 award. One of the recognition of extraordinary support of the Kimmel Professor of Molecular world’s leading neuroscientists, Dr. Tsien School of Medicine’s academic mission. A Immunology, professor of pathology has devoted his career to understanding 1952 alumnus of the New York University and microbiology, and a member of signaling within the brain and the heart; ck; orne R esn i ck; College of Arts and Science, trustee of New the Skirball Institute of Biomolecular he is best known for his studies of calcium York University's board since 1976 and Medicine, was elected to the Institute channels, which drive a multitude of of the Medical Center and School since of Medicine (IOM). Dr. Littman is widely critical processes in the body. T s i en by L • 1998, Mr. Silverstein, along with his wife, recognized for his seminal contributions Klara, recently established the Silverstein to understanding the molecular Scholarship Fund for medical students basis of immune recognition, HIV with an endowment of $5.25 million. He is pathogenesis, T-cell differentiation and president and CEO of Silverstein Properties, selection, and, most recently, the role Inc., a Manhattan-based real estate of commensal bacteria in immune development and investment firm. In July system development and regulation. 2001 Mr. Silverstein signed a 99-year lease Election to the IOM is considered for the World Trade Center for $3.25 billion one of the highest accolades for dollars. Six weeks later, the Twin Towers outstanding professional achievement outh; Dr. Dr. m outh; Wey Li tt m an by M i ke Dr. y; were attacked. Today, he is the driving force and commitment to service in the behind the site’s redevelopment.• fields of medicine and health.• id L ubarsky wi tz by Dav

Dr. Llinás Honored he has made to the neurosciences over ksbury by Jay B ra d by Jay T e w ksbury the course of his career. a Rodolfo Llinás, MD, PhD, Dr. Llinás is known worldwide for the Thomas and Suzanne pioneering magnetoencephalography, Murphy Professor of Neuroscience, a highly sensitive, noninvasive University Professor, and former chair technology for measuring the brain’s of the Department of Physiology electrical activity, and for elucidating and Neuroscience at NYU School how certain brain diseases arise from of Medicine, was awarded the thalamocortical dysrhythmia, the Gold Medal for Science by the disruption of connections between the Spanish National Research Council thalamus and the cortex. (CSIC), the highest distinction the The CSIC is the largest public organization offers. The award institution dedicated to research in d P h i l p Mosko an i n, Si lverste d L arry an G ross m an Dr. d Li n an R e i nberg o f Danny P hotograph recognizes the many contributions Spain and the third largest in Europe. •

NYU Physician WINTER 2012–2013 31 obituary

Robert Porges, MD Robert F. Porges, MD, professor difficult cases. He trained generations of Hospital in San Antonio, Texas. of obstetrics and gynecology, who medical students and delivered generations Dr. Porges came to NYU Langone in 1962, twice served as chair of NYU Langone of mothers and babies with his always-kind, and never left. It was here that he met his Medical Center’s Department of Obstetrics always-compassionate manner.” wife, Felicia Axelrod, MD—then a medical and Gynecology in a career spanning more Scores of patients and their families who student and now a professor of pediatrics and than 50 years, died on November 1. Dr. mourned the loss of Dr. Porges shared these neurology and director of NYU Langone’s Porges, who was 82, had battled lymphoma sentiments. “This wonderful, intelligent, Familial Dysautonomia Program—to whom for several years. caring doctor delivered our daughter and he was married for 47 years. became a close friend for life. At 78, Dr. Porges returned to school to Our family mourns the loss of earn a master’s degree in public health with this extraordinary person who an emphasis on global women’s health. He was a true gentleman: elegant, traveled to Uganda to spend 14-hour days kind, and compassionate,” surgically repairing the fistulas and pelvic wrote Lorraine and Herbert organ prolapses that many women there Podell in an online guest book endure after multiple difficult deliveries. At accompanying Dr. Porges’s NYU Langone, he established the Division obituary in The New York Times. of Global Women’s Health, collaborating A masterful surgeon, Dr. with partners around the world— Porges was director of the particularly in sub-Saharan Africa and the Division of Urogynecology Americas—to improve maternal health in and Reconstructive Pelvic local communities. Surgery. In 2003 he was In late October, as Hurricane Sandy named Distinguished approached, Dr. Porges was a patient in Surgeon by the Society of Tisch Hospital’s Critical Care Unit, gravely Gynecologic Surgeons. Even ill from a relapse of lymphoma. “He and during the final weeks of his family decided he’d go home,” says Dr. his life, physicians sought Keefe. “The power was out at home, but he his advice and requested his had his family by his side.” presence in the operating In addition to his wife, Felicia, Dr. Porges room to assist them with is survived by his son, John, an attorney, challenging cases. and his daughter, Vicki, clinical instructor Born in Vienna, Austria, in pediatrics at NYU Langone, as well as on September 11, 1930, he four grandchildren. • immigrated to the United Dr. Porges (above) and with his wife, Felicia Axelrod, States with his family when he MD, at 2012 Medical Alumni Day. was eight years old. A third- generation physician, Dr. “Dr. Porges was the quintessential old- Porges graduated from Dartmouth College school physician: humble, graceful, and and earned his MD from the State University elegant,” David Keefe, MD, the Stanley of New York (SUNY) Downstate Medical H. Kaplan Professor of Obstetrics and School. After an internship at Beth Israel Gynecology and chair of the Department Medical Center in New York—where his of Obstetrics and Gynecology, told Every father was also on staff—Dr. Porges finished Mother Counts, an organization devoted to his residency training at Jacobi Hospital in making pregnancy and childbirth safer in the Bronx. Dr. Porges served for two years the developing world. “Even in his 80s, he as a staff obstetrician and gynecologist in

was considered the best surgeon for the most the U.S. Air Force, stationed at Wilford Hall P hoto gr aph OF d r. po rg es b y joh n abbott

NYU Physician 32 WINTER 2012–2013 Change Change Change Change Change Change Change Change Change the world…

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